1. Field of the Invention
This invention pertains to ocular pharmacology. More particularly, the invention relates to a method for unexpectedly lessening the incidence of side effects associated with lowering intraocular pressure by administering continuously acetazolamide in controlled, unexpected low dosage amounts to produce both the lessening of side effects and a lowered intraocular pressure. Specifically, the invention pertains to the management of intraocular pressure associated with glaucoma by an improved therapeutic program.
2. Description of the Prior Art
Acetazolamide, or 5-acetamido-1,3,4-thiadiazole-2-sulfonamide, and its therapeutically acceptable salts, is a well-known drug used for lowering elevated ocular pressure. Generically, acetazolamide is an enzyme inhibitor that acts on carbonic anhydrase, the enzyme which catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. Specifically, in the eye, acetazolamide's inhibiting action decreases the secretion of aqueous humor and results in a lowering in intraocular pressure. This reaction is desirable in the management of glaucoma, a physical condition characterized by increased intraocular pressure due to a restricted outflow of the aqueous homor through the aqueous veins and Schlemm's canal. Acetazolamide is particularly indicated for treating primary glaucoma including narrow-angle or acute and wide-angle or chronic simple glaucoma, secondary glaucoma, and preoperatively in acute-angle closure glaucoma where a delay of surgery is desired in order to lower intraocular tension. The preparation of acetazolamide is reported in J. Am. Chem. Soc., Volume 72, pages 4890 to 4892, 1950, in U.S. Pat. Nos. 2,554,816 and 2,980,679. The pharmacology of acetazolamide and the disease glaucoma are described in The Pharmacological Basis of Therapeutics, 4th Edition, by Goodman and Gilman, pages 458 to 459, and pages 851 to 852, 1970, published by the Macmillan Company, New York; and in General Ophthalmology, by Vaughn and Asbury, pages 192 to 209, 1974, published by Lange Medical Publications, Los Altos, Calif.
Presently, the drug acetazolamide is administered for the above conditions in two different oral dosage forms. In one form, acetazolamide is formulated into conventional, standard pharmaceutical tablets, hereafter called the tablet. The tablets are not a sustained dosage form, and they do not provide for the continuous administration of acetazolamide. The tablets contain 125 mg or 250 mg, usually administered at the recommended dose of up to 1 gm per day, to provide both instant acetazolamide and short-term action for reducing aqueous humor secretion at a declining rate of 8 to 12 hours. In the other form, acetazolamide is formulated into sustained release dosage form, hereafter called the sustained release form. The sustained release form contains 500 mg of acetazolamide, and it has a recommended dose of 2 times a day to provide prolonged action for reducing aqueous humor secretion for 18 to 24 hours. The mechanism of sustained release is obtained by progressive variation in the size of coated granules of the drug and in the proportionate quantities of the various sized granules present in the sustained release form, as reported in Am. J. of Opth., Volume 55, pages 323 to 327, 1963. While these prior art forms of administration enjoy wide use for treating glaucoma, serious shortcomings are associated with their use. For example, the tablets dissolve too quickly, and they release their acetazolamide instantaneously; and the sustained release form can exhibit a release rate curve showing exponential decay as a function of time, a rate which is further highly dependent on pH, thereby making it difficult to know how much drug is administered at a given time. The use of the tablet and the sustained release form, can also lead to adverse reactions or side effects, including drowsiness, paresthesias and confusion. These side effects are described in the Medical Dictionary, by Stedman, pages 355, 358, 482 and 1180, published in 1966 by the Williams and Wilkins Co., Baltimore, Md. The common and wide use of acetazolamide with its accompanying high incidence of adverse reactions creates an immediate and pressing need for a new and useful therapeutic method of administering acetazolamide, which method produces the desired pharmaceutical and physiological results while substantially lessening the unwanted reactions associated with modes of acetazolamide administration used by the prior art.